Document Type
Article
Publication Date
11-21-2014
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
Recommended Citation
Fowler BJ, Gelfand BD, Kim Y, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014;346(6212):1000–1003. doi: 10.1126/science.1261754
Copyright
American Association for the Advancement of Science
Included in
Medicinal and Pharmaceutical Chemistry Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutics and Drug Design Commons, Virus Diseases Commons
Comments
This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Science, volume 346, in 2012 following peer review. The definitive publisher-authenticated version is available online at DOI:10.1126/science.1261754.